Redox Chronobiology of Secondary Hyperparathyroidism in Chronic Kidney Disease: Exploring the Circadian–Melatonin–PTH Axis

The novelty of this review lies in its falsifiable, time-resolved framework that integrates the parathyroid molecular clock with melatonin loss, compartment-specific redox failure, and bidirectional PTH–immune signalling rather than treating these mechanisms as parallel associations. Secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) is conventionally attributed to phosphate retention, calcitriol deficiency, hypocalcaemia, and fibroblast growth factor 23 (FGF23) resistance. We synthesise evidence linking mitochondrial reactive oxygen species (ROS), NADPH oxidase (NOX) activation and impaired nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1) signalling to uraemic toxins, inflammation, hyperphosphataemia and dialysis-related oxidant stress. Sustained ROS engage NF-κB, MAPK and endoplasmic reticulum stress pathways that drive parathyroid dysfunction, RANKL-dependent osteoclastogenesis, endothelial dysfunction and vascular smooth-muscle-cell calcification. Inflammation is treated as bidirectional: immune activation amplifies ROS and mineral-tissue injury, while sustained PTH may reciprocally modify monocyte/macrophage, neutrophil and lymphocyte function—an immunological arm that remains hypothesis-generating given sparse, uraemia-confounded evidence in CKD–SHPT. We convert this synthesis into four testable predictions: CKD-stage-specific uncoupling of 24-h PTH and melatonin profiles; redox-dependent loss of chief-cell mineral sensing; cell-specific immune effects of PTH at patient-relevant concentrations; and differential responses to timed versus conventional SHPT therapy. Melatonin may oppose redox and inflammatory injury through receptor-dependent and mitochondrial actions. Because physiological ROS are essential signalling mediators, we emphasise redox balance rather than maximal antioxidant capacity, distinguish human, animal and cellular evidence, and flag supraphysiological PTH, phosphate and melatonin exposures. The proposed axis is a mechanistic research framework, not a basis for routine melatonin, antioxidant or immune-directed therapy pending dedicated CKD outcome trials.